Men who have sex with men (MSM) are disproportionately affected by HIV/AIDS globally. A recent phase 3 clinical trial (iPrEx) showed that oral (PrEP) for HIV prevention with daily oral emtrictabine/tenofovir provided 44% additional protection to high-risk HIV-uninfected MSM. Higher levels of adherence and detection of drug in biological specimens was strongly associated with protective effect. Health departments are currently planning demonstration projects to evaluate whether PrEP can be delivered in community settings. Promoting adherence and reducing risk behaviors will be central to supporting individuals using PrEP in implementation programs. Multi-modal approaches to supporting adherence will likely have the largest and most sustained benefit. Two complementary interventions are particularly promising as components of a combined adherence intervention. First, Next Step Counseling, a client-centered, context-driven counseling approach proved feasible and acceptable when piloted at the end of the iPrEx study. We have recently developed integrated Next Step Counseling (iNSC), merging risk reduction and adherence support counseling, to allow more streamlined delivery in community settings. A second approach, short message system (SMS) support, has been shown to improve antiretroviral adherence rates and lower HIV viral load among HIV-infected patients in Africa. In addition to adherence support, easy-to-use, inexpensive, and accurate tools for monitoring PrEP use in community settings will be critical. In mid 2011, the San Francisco Department of Public Health will launch an 18-month PrEP demonstration project among 400 MSM. In the first phase of this project, we propose to determine the patterns and correlates of adherence and risk behaviors among HIV-uninfected MSM receiving PrEP in a city-sponsored demonstration project. We will also evaluate two novel biological markers of adherence for their utility in monitoring adherence in clinical settings. Data from this first phase will inform the refinement and deployment of a multimodal intervention to promote adherence and reduce risk among MSM PrEP users. In the second phase of this study, we will evaluate the effectiveness of the iNSC+SMS intervention in promoting PrEP adherence and reducing risk behaviors in a randomized clinical trial conducted at the municipal STD clinic in San Francisco. The long term goal of the EPIC study (Enhancing PrEP in Community Settings) is to optimize support of MSM utilizing PrEP in community settings.